Asthma is a disease of rapidly increasing incidence that already affects more than 17 million people in the United States alone. It is of major importance to understand the mechanisms responsible for underlying mechanical and physiological changes that occur during asthma exacerbations. The long-term objective of this project is to expand the understanding of these mechanisms to provide the foundations upon which to develop improved methods for diagnosing, monitoring and managing asthma. Bronchoconstriction is a cardinal feature of asthma, and its spatial distribution within the lungs has wide implications for diagnosis and therapy. An increasing amount of experimental work suggests that the heterogeneous response of the lung cannot be predicted by the summed independent behavior of individual airways. The central hypothesis to this proposal is that such response is a reflection of the integrated response of the lung including serial and parallel interactions amongst airways and parenchyma. This proposal focuses on three key aspects of this hypothesis: 1) the link between parallel heterogeneity in ventilation in asthma with the integrated response of the airway tree, 2) the regional effect of deep inhalations (Dl's) in the development of and recovery from airway obstruction, and 3) the reopening of ventilation defective regions of the lung with Dl's to improve the serial and parallel uniformity of inhaled aerosol drug deposition and effectiveness. The studies will be conducted in healthy persons and patients with asthma and combine non-invasive topographic assessments of lung function, structure and inhaled aerosol deposition, obtained with positron emission imaging and high resolution CT, with global measurements and modeling of lung mechanics. We expect that this detailed anatomical and functional data will provide new insights into the pathophysiology of the disease that will be directly applicable to patient care and will help advance the field of aerosol therapy.